Early Labeling Pays

For a company embarking on the path through drug development, the breadth of possible strategies can be intimidating. Given the increasing cost of moving a drug from idea to market, it is essential for the company to embed efficiencies into the development program. A useful strategy is to consider an ideal end-state for the product and build the program to deliver data to support it.

When planning which studies to perform, which patients to recruit, and which endpoints to include, having an understanding of how the data ultimately will be used can help drive the decision making process. Early definition of product labeling is an ideal mechanism to define these development objectives, unlocking product value by ensuring clinical trial decisions are targeted to maximize product value from day one.

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To understand how and why clinical trial design, labeling, and product value are intimately associated, it is worth considering what constitutes a drug approval. As an example, in the United States, the Code of Federal Regulations states: "FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing, and controls and labeling..."¹ and that "labeling shall contain a summary of the essential scientific information needed for the safe and effective use of the drug."² In other words, we can distill the U.S. NDA review and approval process down to two key deliverables: agreed manufacturing criteria and final approved labeling. In the European Union, the Summary of Product Characteristics "sets out the agreed position of the medicinal product as distilled during the course of the assessment process."³

Since achieving approved labeling is the objective of any clinical program, any development decisions that improve the probability of achieving commercially viable labeling will increase the value of the product. Gathering data that do not drive toward that objective might be an inefficient use of precious resources.

Who writes the label?

Traditionally, product labeling compilation is the responsibility of the regulatory affairs department, compiling the document at a late stage based on a review of data from the studies. Often, this is when shortfalls and gaps are identified, resulting in a substandard submission or delays to allow for generation of additional information.

A more efficient approach is to embark on label development at the beginning of development and form an integrated multidisciplinary team charged with building a target product profile for the drug candidate. The team should include representation from clinical development, commercial, regulatory, and other technical contributory functions such as pharmaceutics development, pharmacology, and toxicology.

Since the label is to be used as a route map for development, even before the first clinical study the sponsor can write the first draft based on the desired end state for the development program. Regardless of the absence of substantial amounts of data, this target label is a useful tool to lay out the optimal final objectives for the development program.

Based on an analysis of the intended therapeutic area, the competitive situation, regulatory guidelines, and market research, the development team can establish critical attributes for the product. These attributes could be based on delivering a new therapy in an area of unmet medical need, or on providing improved efficacy and/or safety, a favorable drug interaction profile, or enhanced dosing convenience.

Once the critical success factors are identified and draft label statements describing them are prepared, the development team can start to build the program to provide data to substantiate each claim. As an example, the inclusion and exclusion of certain patient groups in a clinical trial—such that the study is atypically "healthy"—can have a material impact on the final product due to knock-on precautionary statements in product labeling. While there is a reasonable need to avoid potential confounding safety signals, the patient population should be as representative as the intended treatment population as possible to allow for extrapolation to a real-life clinical situation.

Given the global nature of many development programs, there is also value in using the label as the repository for regional variations in product objectives. Differences in medical practice by region can result in key differences in final product goals, which would impact regulatory and clinical strategy. For example, where standard of care differs by country, alternate comparators may need to be included in clinical studies; this intelligence can be captured as territorial differences in a global labeling template. Similarly, where bridging studies are needed for compliance with ICH guideline E5 (Ethnic Factors in the Acceptability of Foreign Clinical Data),⁴ the target study objectives can be captured in a labeling template.

A simple template highlighting the desired product attribute and describing the experiments required to generate supporting data can be used to track the development of target label statements (see Table 1). Additional criteria, such as relative impact on product value and probability of success, allow for prioritization of attention to individual label statements.

Table 1. A basic six-column template such as the one here can be used by sponsors to track development of target label statements and ensure the entire team, from commercial to regulatory, is on the same page.

Adapting as data emerge

As data are generated, the clinical team can revisit the target label and make updates as necessary. Target label statements are confirmed or rejected based on emerging data, and the overall value of the product and probability for regulatory success can be reevaluated. The development team can alter product strategies depending on the outcome of the reevaluation.

Planning for initial human studies is a useful illustration of how target label statements can be used to inform prioritization of studies and choice of endpoints. A common differentiator in crowded therapeutic areas can be improved dosing convenience to drive improved treatment compliance. Examples include presentation of improved oral formulations, single daily dosing, and absence of "with food" administration. If dosing is a critical factor, appropriate Phase I studies can be designed (e.g., initial pharmacokinetics, food effect) to determine early whether desired label statements can be supported.

Even in situations where appropriate human pharmacokinetics are not forthcoming, the sponsor still has data in hand at an early stage upon which to reconsider the desired product attributes. For example, if oral daily dosing is a critical consideration but the drug has low bioavailability or a short half-life, decisions can be made on reformulation or terminating development and focusing on other candidates.

Clinical efficacy outcomes

One area where a clinical team can impact commercial value is in designing studies such that the outcomes can be effectively explained to the intended prescribing community. In general, the description of clinical studies receives the most attention in development of product labeling since efficacy claims must be supportable from the data provided in a marketing submission. Whether the focus is on patient experience through subjective outcomes measures or on effective graphical presentation of study endpoints, simple, intuitive efficacy measures that can be easily translated to labeling statements will enhance value since they can easily be communicated to prescribers and patients.

Understanding the likely questions from the intended prescribing community can inform the clinical team in understanding how endpoints should be presented in the label. With the label as the basis for educational materials for a medicinal product, the sponsor must ensure clear presentation of key product attributes in labeling, given the limited time available for discussions with prescribers.

Even though identification of target label statements can have a major impact on development programs at early stages, addressing the label later in development can still be a highly beneficial exercise. Including label considerations in discussions on the design and implementation of Phase III studies is particularly useful since the information from pivotal studies will form a major part of any communication on a marketed product. Furthermore, given the financial burden of large Phase III studies, focusing on delivering the target label components will maximize efficiency and reduce cost.

Comparative efficacy

Descriptions of clinical superiority, whether relating to efficacy or safety, can garner significant value for a medicinal product. Not surprisingly, comparative clinical data is a sensitive topic and regulators assess claims of superiority with particular scrutiny. In the United States, there is specific legislation that describes the evidence needed to claim that a drug is safer or more effective than another.⁵ Superiority statements not in line with approved labeling are frequently the basis of regulatory action, and FDA Warning Letters relating to inappropriate superiority claims are common. To avoid the regulatory pitfalls, clinical teams must think about how superiority information is to be communicated and design studies accordingly.

Superiority labeling is a high hurdle and therefore clinical studies must be designed appropriately, focusing on the specific claims to be supported. Prior to initiating superiority studies, it is highly recommended to solicit regulators' opinion in order to achieve some level of buy-in to the intended program. Sponsors also need to carefully evaluate the risks and complexity of conducting comparative studies, such as relatively large sample sizes, and the implications of nonsuperiority outcomes.

Regulatory input

In the draft guidance issued in March 2007,⁶ FDA acknowledged that draft labeling, in the form of a Target Product Profile (TPP), has advantages in orienting the Agency to sponsor's development goals. It also serves as a mechanism to streamline review discussions by focusing explicitly on the goals of the development program.

The guideline, "Target Product Profile—A Strategic Development Process Tool," includes a suggested template and examples of situations where a TPP has been advantageous to development programs and where omission of a TPP has had disadvantages. Despite its potential advantages, sharing a TPP with FDA has not been universally embraced by sponsors. They may understand the utility of a draft label as a tool for internal use but show residual concern at sharing a desired end-state with regulators.

While there is no formal codified mechanism akin to the TPP outside the United States, target label statements can be included in briefing materials for key regulatory authority interactions (such as EU Scientific Advice), if the sponsor sees value in such discussion at milestone meetings.

Risk management tool

Finally, labeling also serves as a central component of risk management for a product. In this context, sponsor companies have the opportunity to fine tune precautionary labeling statements as data become available. In this way, risk management becomes integral to the drug development program rather than a last minute consideration at marketing authorization submission or during label negotiation.

There are several examples, particularly in the European Union, where exclusion of groups of patients from Phase III trials has resulted in precautionary statements due to the absence of specific safety data. While it is prudent to exclude patients with particular co-morbidities to reduce confounding safety signals, clinical trial sponsors should consider the potential labeling impact.

In the United States, Risk Evaluation and Mitigation Strategies (REMS) are being required more frequently. One key REMS component, the Medication Guide, is used to inform patients about key risks and is approved as a component of product labeling.⁷ Thus, establishing label criteria during development can extend beyond definition of prescribing information. Key safety data emerging during development can be integrated into the Medication Guide and label in parallel. Other components of a REMS, such as a Communication Plan, also can be advanced alongside labeling as the understanding of the critical safety parameters develops. In this way, consistency in approach between labeling and other risk management activities is assured.

Summary

Forming a multidisciplinary team early in development to build a target label and using that label as the guide for drug development allows the sponsor to focus on the desired end-state throughout development. Thus, clinical studies can be designed specifically to unlock the inherent value in the drug candidate, ensuring resources are applied in the most efficient manner.

Mike Page is Senior Director of Regulatory Affairs at United BioSource Corporation, 2200 Commonwealth Blvd, Suite 100, Ann Arbor, MI 48105, email: mike.page@unitedbiosource.com.

References

1. Code of Federal Regulations, Title 21, Part 314, Section 105(c) (U.S. Government Printing Office, Washington, DC).

2. Code of Federal Regulations, Title 21, Part 201, Section 56(a) (U.S. Government Printing Office, Washington, DC).

3. A Guideline on Summary of Product Characteristics, September 2009 (European Commission Enterprise and Industry Directorate-General, Brussels, Belgium).

4. Ethnic Factors in the Acceptability of Foreign Clinical Data, February 1998 (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland).

5. Code of Federal Regulations, Title 21, Part 4, Section 202.1(e)(6)(ii) (U.S. Government Printing Office, Washington, DC).

6. Food and Drug Administration, Guidance for Industry and Review Staff Target Product Profile—A Strategic Development Process Tool (FDA, Rockville, MD, March 2007).

7. Code of Federal Regulations, Title 21, Part 4, Section 208.3(h) (U.S. Government Printing Office, Washington, DC).